New approach is promising for controlling breast cancer progression to aggressive disease

Doctors currently struggle to determine whether a breast tumor is likely to shift into an aggressive, life-threatening mode—an issue with profound implications for treatment. A mechanism has been identified through which mitochondria, the powerhouses of a cell, control tumor aggressiveness. Based on these findings, researchers at Scripps Research Institute developed a simple treatment that inhibits cancer progression and prolongs life when tested in mice. The research team hopes to proceed quickly to human clinical trials to test this new approach using drugs already in use for other conditions.

Past research from this team had suggested that mutations affecting mitochondria, which are key to energy production in cells, strongly influence whether a tumor becomes aggressive. The research team chose to investigate mitochondrial complex I, a specific protein complex that determines the energy output of cellular respiration. The team discovered that the balance of key metabolic cofactors processed by complex I—specifically, nicotinamide adenine dinucleotide (NAD+) and NADH, the form it takes after accepting a key electron in the energy production cycle—was disturbed in aggressive breast cancer cells.

To find out if the balance of NAD+ and NADH was critical for tumor cell behavior, the team inserted a yeast gene into cancer cells that caused a shift toward more NAD+. To the scientists’ amazement, this shift caused the tumor cells to become less aggressive.

To confirm and extend the initial findings, the team altered genes tied to NAD+ production. The resulting shift again showed that higher NADH levels resulted in more aggressive tumors, while increased NAD+ had the opposite effect.

The next logical step was to find a simple way to enhance the critical NAD+ level therapeutically. So the team explored what would happen if mice with breast cancer were fed water spiked with nicotinamide, a precursor for NAD+ production. The scientists found cancer development was dramatically slowed down, and the mice lived longer.

“In animal models at various stages, we see that we can actually prevent progression of the disease,” said Brunhilde Felding-Habermann, PhD, also of Scripps. This research was published in The Journal of Clinical Investigation (2013; doi:10.1172/JCI64264).

Now the group is working toward human trials to learn whether nicotinamide or other NAD+ precursors will have similarly impressive results in humans. NAD+ precursors are already used for other purposes, such as controlling cholesterol levels; achieving approval for human clinical trials should be simpler than is normally the case.

“It is not a totally new treatment that would need to be tested for toxicity and side effects like a new drug,” said Felding. “And we already know the precursors can be easily ingested.”

If manipulating the NAD+/NADH ratio in humans has the same effect as it did in mice, the results could be profound. Such treatment could benefit people at risk of developing aggressive breast cancer, offer complimentary treatment to chemotherapy and radiation therapy to avoid disease recurrence, and maybe even provide a preventive treatment for women with a family history of breast cancer.